The article “Tailoring Gene Editing with Machine Learning: A Breakthrough in CRISPR-Cas9 Enzyme Engineering” discusses how researchers from Mass General Brigham have harnessed machine learning to revolutionize the field of genome editing. By developing a machine learning algorithm called PAMmla, they’ve predicted the properties of over 64 million genome editing enzymes, significantly expanding our repertoire of effective and safe CRISPR-Cas9 enzymes.

CRISPR-Cas9 enzymes are powerful tools for editing genes, but their traditional application can have off-target effects, modifying DNA at unintended sites in the genome. The researchers’ novel approach uses machine learning to better predict and tailor these enzymes, ensuring greater specificity and accuracy in gene editing. This scalable solution has the potential to transform our understanding of genetic conditions and unlock new therapeutic targets.

The study showcases the power of PAMmla by demonstrating its utility in precise editing disease-causing sequences in primary human cells and mice. The researchers have also made a web tool available for others to use this model, enabling the community to create customized enzymes tailored for specific research and therapeutic applications.

Ben Kleinstiver, PhD, and Rachel A. Silverstein, PhD candidate, are leading authors on this study, highlighting the potential of machine learning in expanding our capabilities in gene editing. This breakthrough has significant implications for the field, offering a new era of precision and safety in genome editing technology.

Unlocking Cellular Secrets: New Technique Expands Tissues for Mass Spectrometry Imaging

For biologists, seeing is believing. But sometimes biologists face a daunting challenge: visualizing the intricate world within intact tissue samples, down to the level of single cells. Detecting hundreds or thousands of biomolecules – from lipids to metabolites to proteins – in their native environment allows researchers to better understand their functions and interactions.

Traditional imaging methods, including most types of microscopy, provide a view of molecules inside cells but can only track a select handful at one time. Other methods, like regular mass spectrometry, can detect hundreds of molecules but don’t work on intact samples, so researchers can’t see how the biomolecules are oriented.

One promising technique – mass spectrometry imaging – overcomes some of these challenges. It allows researchers to see hundreds of molecules at once in intact tissues. However, it doesn’t have high enough resolution to allow detection at the single cell level.

This was the problem Janelia Senior Group Leader Meng Wang faced. Wang and her team study the fundamental mechanisms behind aging and longevity, and they wanted to detect many different biomolecules in intact tissues to understand how the components change as tissues age.

“Knowing at each specific location what molecules are there and what is in the neighboring cells is very important for any kind of biological question,” Wang says.

Luckily, Wang’s lab is down the hall from Janelia Principal Scientist Paul Tillberg. Tillberg co-invented expansion microscopy as a graduate student at MIT. The method uses a swellable hydrogel material to expand samples uniformly in all directions to a point where fine details, like sub-organelle structure, can be detected with a conventional microscope.

Now a decade old, the expansion process is being applied to other methods outside traditional microscopy. Wang, Tillberg, and their collaborators at Janelia and the University of Wisconsin-Madison wanted to see if they could use expansion to overcome mass spectrometry imaging’s spatial resolution problem.

The result is a new method that expands tissue samples gradually without having to degrade them at the molecular level, as happens in the original expansion process. By expanding the intact samples in all directions, researchers can use mass spectrometry imaging to simultaneously detect hundreds of molecules at the single cell level in their native locations.

“This lets you have an untargeted look in the molecular space, and we are trying to bring it closer to what microscopy can do in terms of spatial resolution,” Tillberg says.

The team used the new technique to delineate the specific spatial patterns of small molecules in different layers of the cerebellum. They found that these molecules – including lipids, peptides, proteins, metabolites, and glycans – are not uniformly distributed, as previously thought. Moreover, they found that each specific layer of the cerebellum has its own signature of lipids, metabolites, and proteins.

The team was also able to detect biomolecules in kidney, pancreas, and tumor tissues, demonstrating that the method can be adapted for many different tissue types. In tumor tissues, they were able to visualize large variations in biomolecules, which could be useful for understanding the molecular mechanisms of tumors and potentially aid in drug development.

“When you can see these biomolecules, then you can start to understand why they have such patterns and how that is related to function,” says Wang. She believes the new technology will allow researchers to track these patterns during development, aging, and disease to understand how different molecules contribute to these processes.

Because the new method doesn’t require adding hardware to an existing mass spec imaging system, and the expansion technique is relatively easy to learn, the team hopes it will be used by many labs around the world. They also hope the new technique will make mass spectrometry imaging a more useful tool for biologists and have laid out a detailed description of the new method and a roadmap for adapting it to other tissue types.

“We wanted to develop something that did not require specialized instruments or procedures, but can be broadly adopted,” Wang says.

Rewritten Article:

Scientists have made a groundbreaking discovery that could revolutionize the production of green hydrogen, a crucial component for a sustainable energy future. Researchers have found that a cage-structured material, previously unknown as an electrocatalyst, can outperform existing nickel-based catalysts in electrolytic hydrogen production. This breakthrough has significant implications for the chemical industry and our transition to renewable energy sources.

The study, published in Angewandte Chemie, investigates the suitability of clathrates – materials characterized by a complex three-dimensional cage structure – as catalysts for oxygen evolution reaction (OER) in electrolysis. Clathrates have shown promise in various applications, such as thermoelectrics and superconductors, but their potential as electrocatalysts has remained unexplored until now.

Dr. Prashanth Menezes and his team at the Technical University of Munich synthesized Ba₈Ni₆Ge₄₀ clathrates, which they then tested as OER catalysts in aqueous electrolytes. The results were astonishing: the clathrate sample exceeded the efficiency of nickel-based catalysts at a current density of 550 mA cm⁻², a value commonly used in industrial electrolysis. Moreover, its stability was remarkable, with activity remaining high even after 10 days of continuous operation.

To understand why this material performed so well, the researchers employed a combination of experiments, including in situ X-ray absorption spectroscopy (XAS) at BESSY II and basic structural characterization at the Freie and Technische Universität Berlin. Their analysis revealed that the clathrate particles undergo a structural transformation under an electric field: germanium and barium atoms dissolve out of the former three-dimensional framework, leaving behind highly porous, sponge-like nanolayers of nickel that offer maximum surface area.

“This transformation brings more and more catalytically active nickel centres into contact with the electrolyte,” says Dr. Niklas Hausmann from Menezes’ team. “We were actually surprised by how well these samples work as OER catalysts. We expect that we can observe similar results with other transition metal clathrates and that we have discovered a very interesting class of materials for electrocatalysts.”

This breakthrough has significant implications for the production of green hydrogen, which is seen as an essential building block for a sustainable energy future. With this new material, researchers may be able to develop more efficient and robust OER catalysts, enabling faster and more cost-effective production of green hydrogen.